PC12 cells provide a model well suited for the study of events associated with peptide factor-stimulated neu- ronal differentiation. PC12 cells possess high affinity receptors for/and respond to the neurotrophin, nerve growth factor (NGF). Upon addition of NGF to PC12 cultures, cellular replication ceases and once-round cells de- velop a phenotype characteristic of sympathetic neurons replete with electrically excitable neuritic processes possessing neurotransmitter-containing axonal terminals. While the precise sequence of events responsible for mediating this profound, neurodifferentiative biologic signal remains to be determined, it is clear that protein phosphorylation is a critical component. The cascade of events elicited by NGF is initiated by ligand- induced ac- tivation of the high affinity, NGF receptor, p140trkA. This proto-oncogene product is a tyrosine kinase. Once activated, the receptor dimerizes, autophosphorylates on tyrosine residues and recruits important signal trans- ducing molecules through direct protein-protein interactions. In addition to the neurotrophin receptor, p140trkA, PC12 cells express receptors for numerous other peptides including the mitogen, epidermal growth factor (EGF) and the neuroactive peptide, vasoactive intestinal peptide (VIP). Like p140trkA, the receptor for EGF is a tyrosine kinase. Upon addition of EGF to PC12 cells, virtually all the biochemical events that immediately follow, particularly protein tyrosine phosphorylation of key signalling substrates, are identical to those observed for NGF. However, unlike NGF, EGF is not capable of stimulating PC12 cells to undergo neuronal differentiation. Addition of VIP to PC12 cells also stimulates protein phoshor- ylation. Phosphate is added primarily to serine residues and is presumably mediated by activation of adenylate cyclase, resulting in enhanced generation of cyclic AMP leading to activation of cyclic AMP-dependent protein kinase A. Commensurate with the addition of VIP is the sprouting of short, neuritic processes. At one time, based on results obtained using membrane-permeable analogs of cyclic AMP, it was suggested that protein kinase A was involved in the induction of NGF-induced neurite outgrowth. Unlike NGF, this is a transcription- independent process. Qualitatively, the processes induced by VIP are distint from the more fully extended, more complexely arborized neurites elicited by NGF. Neither EGF nor VIP, alone, elicits a robust neuronal differentiative responsive when added to PC12 cells, how- ever, when added together, PC12 cells undergo a morphologic differentiation analogous to that observed for NGF. Presently, a number of parameters including MAP kinase phosphorylation and activation, neurofilament induction, and tyrosine hydroxylase expression are being evaluated to determine whether the combination of EGF and VIP elicits responses biochemically equivalent to those characteristic of NGF.